COVID infection equips the body to fight off the flu

More than 200 viruses can infect humans, and most of us will encounter several of them throughout our lives. But how do these infections influence our immune system’s ability to respond to other viruses?

Does encountering one virus weaken or strengthen our defenses against another? Or does it have an entirely different effect? These questions were the focus of a new study by scientists at Rockefeller University.

The research was conducted in the Laboratory of Virology and Infectious Disease led by Charles M. Rice, and Weill Cornell Medicine’s Laboratory of Epigenetics and Immunit led by Steven Z. Josefowicz. 

Immune system and prior Infections 

The study reveals fascinating insights about how our immune system adapts to prior infections.

By studying mice that were first infected with SARS-CoV-2 and then exposed to the influenza A virus, the researchers made a surprising discovery: recovering from COVID had a protective effect against the severe outcomes of the flu. 

This memory response, however, came from an unexpected part of the immune system – macrophages.

Immune cells develop a memory

The researchers found that epigenetic changes in macrophages – innate immune cells known for their early response to threats – had developed a form of “memory” following the initial COVID infection. 

This allowed the macrophages to mount a stronger defense against the flu virus, even though it’s unrelated to the COVID virus. Immunological memory was long thought to be a trait exclusive to adaptive immune cells like T cells. 

However, this study challenges that notion by showing that macrophages can “remember” and defend against future threats. Intriguingly, this memory wasn’t tied to any one specific virus.

Immune memory following COVID infection 

“Immune memory is critical to fending off recurring diseases caused by pathogen,” said study first author Alexander Lercher, a postdoctoral fellow in Rice’s lab.

“What’s exciting about our study is that we’ve discovered a broadly effective antiviral immune memory in macrophages following SARS-CoV-2 infection that can reduce disease caused by a completely different virus.”

“A more detailed understanding of these mechanisms could aid development of new therapeutic strategies that cover a range of respiratory viruses.”

Exciting implications of the research 

Josefowicz said it was exciting to delve into the epigenetic mechanisms encoding this general antiviral memory. 

“The implications are profound. If we can walk around with months-long bolstered immunity after a season’s worth of respiratory infections, what are the implications for seasonal trends in these infections?” said Josefowicz.

“How much human variance – genetic and epigenetic – exists in these pathways?” 

Innate immune memory responses

When a virus invades the body, cytokines signal innate immune cells, like macrophages, to respond quickly and attack. 

This initial response is followed by a more tailored defense from adaptive immune cells, like T cells, which recognize specific virus antigens and store that memory for future infections.

But recent studies, including this one, show that innate immune responses can also develop memory. 

For example, people who received the Bacillus Calmette-Guérin (BCG) vaccine – originally designed to protect against tuberculosis – demonstrated innate immune memory responses that lasted for months, offering protection against unrelated infections.

However, how this broad immune memory forms has remained a mystery. 

COVID and flu infections

In 2020, Lercher began investigating this phenomenon using two widely circulating viruses: SARS-CoV-2 and influenza A, the latter of which has troubled humanity since the 1918 pandemic.

Lercher and his colleagues focused their research on the long-term consequences of COVID-19 on the respiratory system, particularly cells in the lungs. 

The experts found that alveolar macrophages, located in the airways, had undergone an epigenetic reprogramming after infection. The chromatin around antiviral genes became more accessible, which essentially primed these genes for quick activation in future infections.

This discovery wasn’t limited to mice. When the team analyzed blood samples from people who had recovered from mild COVID, they found similar epigenetic changes in monocytes – the precursors to macrophages.

Controlled inflammatory responses after COVID

The result of this epigenetic shift? These immune cells could “remember” past infections, enabling them to respond more effectively to future viral invasions.

Thanks to this new immune memory, the macrophages in the lungs of COVID-recovered mice were better equipped to fight off influenza A. 

Compared to mice without previous COVID infections, these mice exhibited fewer symptoms, such as less weight loss and more controlled inflammatory responses. Their mortality rates were also lower.

“The fact that viral RNA alone seems to be able to trigger memory in macrophages lays the foundation of this memory being antigen independent,” Lercher explained. “They’re recognizing a pattern that is shared by many viruses, unlike a virus-specific antigen.”

The team confirmed this by exposing the mice to a synthetic mimic of an RNA virus and observing similar memory responses.

Interestingly, when battling the flu, these memory-primed macrophages outperformed adaptive T cells. “The macrophages are really the ones driving this response,” Lercher said.

Milder flu symptoms after COVID infection 

To test just how robust this memory was, the team extracted macrophages from COVID-recovered mice and transferred them into naive mice. They then exposed these mice to influenza A.

Sure enough, the recipient mice showed milder flu symptoms than mice that received naive macrophages.

“The naive mice with the implanted recovered macrophages fared better against influenza than mice implanted with naive macrophages,” Lercher reported.

Future protection against viruses

Looking forward, the researchers hope to pinpoint the key factors responsible for this innate immune memory. 

“In an ideal world, we would find one or a few factors that lead to this memory formation in macrophages and other innate cells, and then exploit it to develop therapies that offer broad protection against many viruses,” said Rice.

This approach could be especially valuable during future pandemics. If there were a new emerging pathogen on the horizon, noted Lercher, it would be nice to have a therapy that boosted your general antiviral immunity for the next month or so. 

“That’s still very far away, and a lot more research needs to be done, but I think it could be possible one day,” Lercher concluded.

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